Synthesis of (+)-juruenolide C: Use of sequential 5-exo-digonal radical cyclization, 1,5-intramolecular hydrogen transfer, and 5-endo-trigonal cyclization

Article abstract of DOI:10.1021/jo010206y

Acetylenic alcohol 10 was converted successively into silane 11 and phenylseleno carbonate 14. On treatment with Ph₃SnH, the latter underwent 5-exo-digonal radical cyclization, intramolecular hydrogen transfer, and 5-endo-trigonal cyclization, yielding 15. Conversion of the lactone into the lactol benzyl ether 17, carbon-silicon bond cleavage, and regeneration of the lactone carbonyl gave (+)-juruenolide C (1).

Full text of DOI:10.1021/jo010206y

J . Org. Chem. 2001, 66, 4841-4844
4841
Syn th esis of (+)-J u r u en olid e C: Use of Sequ en tia l 5-Exo-Digon a l
Ra d ica l Cycliza tion , 1,5-In tr a m olecu la r Hyd r ogen Tr a n sfer , a n d
5-En d o-Tr igon a l Cycliza tion
Derrick L. J . Clive* and Elena-Simona Ardelean
Chemistry Department, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
derrick.clive@ualberta.ca
Received February 26, 2001
Acetylenic alcohol 10 was converted successively into silane 11 and phenylseleno carbonate 14.
On treatment with Ph3SnH, the latter underwent 5-exo-digonal radical cyclization, intramolecular
hydrogen transfer, and 5-endo-trigonal cyclization, yielding 15. Conversion of the lactone into the
lactol benzyl ether 17, carbon-silicon bond cleavage, and regeneration of the lactone carbonyl gave
(+)-juruenolide C (1).
The γ-lactone juruenolide C (1) was isolated1,2 from
Sch em e 1
seedlings and micropropagated leaves of Virola surina-
mensissa myristicaceous tree that thrives on river banks
in Amazonia. The compound is a member of a group of
related substances differing in the length of the chain
that connects the piperonyl and lactone units.1,4 The
amount of 1 in the plant source appears to be related to
the growth rate,1 although the mechanistic basis for this
is not known. Compound 1 has been found to have
antifungal activity against Cladiosporium cladisporio-
ides, but it is 10 times less potent than nystatin.4
this sequence, but in examples where stereochemical
adjustment of the final cascade product was required;7b
in the present case, no such modifications are needed,
and we report a short route to (+)-1.
Analysis of structure 1 in terms of the general method
summarized in Scheme 1 shows that appropriate starting
materials are the known aldehyde 78 and the acetylene
8. Previous work7a,c had indicated that a triethylsilyl
protecting group (see 7) was suitable, as it can be
removed (see below) in the presence of the t-Bu2SiH group
that plays a central role in the radical cascade (see
Scheme 1). The acetylene 8 was readily made (CBr4,
Ph3P, Et3N, -78 °C to room temperature, 87%; BuLi, -78
Simple, naturally occurring γ-lactones bearing three
contiguous substituents with the 3R,4R,5â relationship
found in 1 appear to be rare.5 This particular stereo-
chemistry is precisely that which is directly accessible6
by appropriate modification of the general radical cas-
cade7 summarized in Scheme 1, where the chain linking
the radical center to the acetylene can carry substituents
and/or incorporate heteroatoms. Previous work in this
laboratory has illustrated some synthetic applications of
(1) (a) Lopes, N. P.; Franc¸a, S. de C.; Pereira, A. M. S.; Maia, J . G.
S.; Kato, M. J .; Cavalheiro, A. J .; Gottlieb, O. R.; Yoshida, M.
Phytochemistry 1994, 35, 1469-1470. (b) Lopes, N. P.; Blumenthal,
E. E. de A.; Cavalheiro, A. J .; Kato, M. J .; Yoshida, M. Phytochemistry
1996, 43, 1089-1092.
(2) The absolute stereochemistry was assigned by comparison with
that of juruenolide (see ref 3).
(3) Vieira, P. C.; Yoshida, M.; Gottlieb, O. R.; Filho, H. F. P.; Nagem,
T. J .; Filho, R. B. Phytochemistry 1983, 22, 711-714.
(4) Lopes, N. P.; Kato, M. J .; Yoshida, M. Phytochemistry 1999, 51,
29-33.
(5) For some other examples, retrieved by a search of the Beilstein
database, see ref 3 and: (a) Hikino, H.; Nomoto, K.; Takemoto, T.
Phytochemistry 1971, 10, 3173-3178. (b) Epstein, W. W.; Gaudioso,
L. A. J . Org. Chem. 1979, 44, 3113-3117. (c) Ravi, B. N.; Wells, R. J .
Aust. J . Chem. 1982, 35, 105-112. (d) Huneck, S.; Tønsberg, T.;
Bohlmann, F. Phytochemistry 1986, 25, 453-459. (e) Maeda, M.;
Kodama, T.; Tanaka, T.; Yoshizumi, H.; Takemoto, T.; Nomoto, K.;
Fujita, T. Tetrahedron Lett. 1987, 28, 633-636. (f) Magri, F. M. M.;
Kato, M. J .; Yoshida, M. Phytochemistry 1996, 43, 669-672. (g) Lopes,
N. P.; Silva, D. H. S.; Kato, M. J .; Yoshida, M. Phytochemistry 1998,
49, 1405-1410.
(6) For other routes to 4-hydroxy-3,5-disubstituted γ-lactones with
3R,4R,5â relative stereochemistry, see, for example: (a) Heathcock, C.
H.; Young, S. D.; Hagen, J . P.; Pirrung, M. C.; White, C. T.; VanDer-
veer, D. J . Org. Chem. 1980, 45, 3846-3856. (b) Kozikowski, A. P.;
Ghosh, A. K. J . Org. Chem. 1984, 49, 2762-2772. (c) Schlessinger, R.
H.; Tata, J . R.; Springer, J . P. Tetrahedron Lett. 1987, 28, 5423-5426.
(d) Mulzer, J .; Schulze, T.; Strecker, A.; Denzer, W. J . Org. Chem. 1988,
53, 4098-4103. (e) Rotella, D. P.; Li, X. Heterocycles 1990, 31, 1205-
1211. (f) Hanessian, S.; Le´ger, R.; Alpegiani, M. Carbohydr. Res. 1992,
228, 145-156. (g) Mukai, C.; Kataoka, O.; Hanaoka, M. J . Org. Chem.
1993, 58, 2946-2952.
(7) (a) Clive, D. L. J .; Yang, W.; MacDonald, A.; Wang, Z.; Cantin,
M. J . Org. Chem. 2001, 66, 1966-1983 and references cited therein.
(b) Sannigrahi, M.; Mayhew, D. L.; Clive, D. L. J . J . Org. Chem. 1999,
64, 2776-2788. (c) Clive, D. L. J .; Yang, W. J . Chem. Soc., Chem.
Commun. 1996, 1605-1606. (d) Clive, D. L. J .; Cantin, M. J . Chem.
Soc., Chem. Commun. 1995, 319-320.
(8) Cainelli, G.; Panunzio, M.; Bandini, E.; Martelli, G.; Spunta, G.
Tetrahedron 1996, 52, 1685-1698.
10.1021/jo010206y CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/20/2001

4842 J . Org. Chem., Vol. 66, No. 14, 2001
Clive and Ardelean
pounds13,14 show that J 4,5 is typically ca. 5-6 Hz for cis
substitution (cf. 20) and ca. 7-8 Hz for trans substitution
(cf. 21) on the dioxolane ring. Later in the synthesis (see
below), the stereochemistry was again confirmed by
TROESY NMR measurements on compound 17.
Sch em e 2
Silylation of 10 with t-Bu2SiHCl then afforded 11 in
82% yield. In the two steps leading to 10 and 11, some O
f O migration of the Et3Si group was observed. Selective
removal of the Et3Si group (CF3CO2H, THF-water, 87%)
gave alcohol 12, which was not susceptible to silyl
migration. The free hydroxyl of 12 was acylated with 1,1′-
carbonyldiimidazole (Im2CO), and the resulting carbam-
ate 13 was treated with PhSeH in refluxing ClCH2CH2Cl.
The desired phenylseleno carbonate 14 could then be
isolated in 74% overall yield.15 Attempts to convert 12
into the corresponding chloroformate, for subsequent
reaction with PhSeNa, gave erratic results, but the route
via 13 is reliable. Slow addition of a benzene solution of
Ph3SnH and AIBN to a refluxing solution of phenylseleno
carbonate 14 in the same solvent served to generate the
expected acyl radical (14 f 14a ) and initiate the desired
cascade of transformations (14a f 14b f 14c), ulti-
mately affording lactone 15 (79%).
a
Key: (i) t-Bu2SiHCl, imidazole, CH2Cl2, 18 h, 82%; (ii)
CF3CO2H, THF-water, 2 h, 87%; (iii) Im2CO, ClCH2CH2Cl, 4 h;
(iv) PhSeH, ClCH2CH2Cl, reflux, 12 h, 74% from 12; (v) Ph3SnH,
AIBN, addition over 7 h, PhH, reflux, 79%; (vi) DIBAL-H, PhMe,
-78 °C, 15 min, ca. 100%; (vii) BnOH, CH2Cl2, TsOH‚H2O, 10 min,
98% from 15; (viii) Bu4NF, THF-DMF, 60 °C, 4 h, 71%; (ix) Pd/C,
MeOH, H2 (balloon), 15 min; (x) Fe´tizon’s reagent, PhH, reflux, 4
h, 53% from 17.
At this point, we experienced some difficulty in cleaving
the carbon-silicon bond of 15, but soon found that
conversion of the lactone into a lactol ether allowed
smooth desilylation. Reduction of lactone 15 (DIBAL-H)
and conversion of the resulting lactol 1616 into the
corresponding benzyl ether (BnOH, TsOH‚H2O, 98%
overall) gave material (17) that underwent the desired
C-Si cleavage (17 f 18) when treated with Bu4NF in
warm THF-DMF (ca. 71%). Benzyl ether 17 was a single
isomer, and the indicated stereochemistry was confirmed
by TROESY measurements. Hydrogenolysis of crude 18
released the lactol functional group (18 f 1917), and
oxidation with Fe´tizon’s reagent gave (+)-juruenolide C
(1). We had initially converted 16 into the derived
O-methyl ethers [epimeric at C(4)] but were unable to
regenerate the lactols efficiently after C-Si cleavage;18
use of a benzyl ether solved this problem.
°C, 95%)9 from the known aldehyde 9,10,11 which was itself
easily prepared by standard methods.10
Treatment of acetylene 8 with BuLi and reaction with
aldehyde 7 gave (59%) the acetylenic alcohol 10 (Scheme
2) as the major (ca 2.5:1) product, whose stereochemistry
was assigned by analogy with related12 acetylide addi-
tions. The assignment was confirmed by desilylation and
conversion of the resulting diol into the ketal 20. The
minor alcohol (10′, not shown in Scheme 2) from the
acetylide addition was likewise converted into ketal 21.
1H NMR analysis of both ketals showed that J 4,5 for 20
was 5.5 Hz, and the corresponding value for 21 was 8.1
Hz. Published coupling constants for suitable model com-
1
Our synthetic 1 had H and 13C NMR spectra that were
identical, within experimental error, with the published
data, but the optical rotation differed from the reported
value. We found [R]546 +26 (c 0.3, MeOH) [lit.1a [R]25
546
(13) Models for trans ketal: Mukai, C.; Kim, J . S.; Sonobe, H.;
Hanaoka, M. J . Org. Chem. 1999, 64, 6822-6832. Compounds 5a -c
of this publication were used as the models.
(14) Model for cis ketal: Yadav, J . S.; Chander, M. C.; Reddy, K. K.
Tetrahedron Lett. 1992, 33, 135-138. Compound 10 of this publication
was used as the model.
(15) Cf. Tian, F.; Montchamp, J .-L.; Frost, J . W. J . Org. Chem. 1996,
61, 7373-7381.
(16) Compound 16 is a single lactol, but the indicated C(4) stereo-
chemistry is an arbitrary assignment.
(9) Grandjean, D.; Pale, P.; Chuche, J . Tetrahedron Lett. 1994, 35,
3529-3530. Cf. Clive, D. L. J .; He, X.; Postema, M. H. D.; Mashimbye,
M. J . J . Org. Chem. 1999, 64, 4397-4410.
(10) Rotherham, L. W.; Semple, J . E. J . Org. Chem. 1998, 63, 6667-
6672.
(11) Aldehyde 9 was made by PCC oxidation (92-95%) of the
corresponding alcohol; the procedure of ref 10 calls for Swern oxidation
(95%).
(12) Cf. Hirama, M.; Shigemoto, T.; Itoˆ, S. J . Org. Chem. 1987, 52,
3342-3346.
(17) We did not establish if the material was a single isomer or a
mixture of two; the indicated C(2) stereochemistry is arbitrary.
(18) We tried the following conditions: TsOH‚H2O-THF-water,
room temperature; CF3CO2H-THF-water, 0 °C or at room temper-
ature; AcOH-THF-water, room temperature.

Synthesis of (+)-J uruenolide C
J . Org. Chem., Vol. 66, No. 14, 2001 4843
as a colorless oil. The other isomer that was formed was not
+3.7 (MeOH)]. The optical purity of our synthetic jurue-
nolide C rests on the optical purity of alcohol 10; that
compound was found to have an ee of >98% (see Sup-
porting Information). The magnitude of the optical rota-
tion previously reported for 1 is, however, a tentative
value,1a as insufficient material was available for a
reliable measurement. If the dextrorotatory nature of the
compound is accepted, our synthesis confirms the as-
signed absolute configuration.
obtained pure, and was discarded. Compound 10 had: [R]D
-21.26 (c 1.35, CHCl3); FTIR (CHCl3 cast) 3571, 2933 cm-1
;
1H NMR (CDCl3, 360 MHz) 0.62 (q, J ) 7.9 Hz, 6 H), 0.97 (t,
J ) 7.9 Hz, 9 H), 1.23 (d, J ) 6.2 Hz, 3 H), 1.25-1.61 (m, 8
H), 2.21 (td, J ) 6.9, 2.5 Hz, 2 H), 2.38 (d, J ) 4.7 Hz, 1 H),
2.53 (apparent t, J ) 7.5 Hz, 2 H), 3.90 (dq, J ) 6.2, 3.6 Hz,
1 H), 4.27 (m, 1 H), 5.91 (s, 2 H), 6.60-6.78 (m, 3 H); 13C NMR
(CDCl3, 100.6 MHz) δ 4.9 (t′), 6.8 (q′), 17.8 (q′), 18.7 (t′), 28.5
(t′), 28.6 (t′), 28.7 (t′), 31.6 (t′), 35.6 (t′), 67.1 (d′), 71.0 (d′), 78.0
(s′), 86.8 (s′), 100.7 (t′), 108.0 (d′), 108.4 (d′), 121.0 (d′), 136.6
(s′), 145.4 (s′), 147.5 (s′); exact mass (electrospray) m/z calcd
for C24H38NaO4Si 441.243708, found 441.243724.
Exp er im en ta l Section
Gen er a l P r oced u r es. Unless stated to the contrary, the
general procedures used previously19 were followed. The
symbols s′, d′, t′, and q′ used for 13C NMR signals indicate zero,
one, two, or three attached hydrogens, respectively. The
expression “apparent triplet” indicates nonbinomial relative
intensity of the signals.
In a similar experiment, done on almost the same scale, a
portion of the crude product from the acetylide addition was
desilylated and the diol mixture was ketalized (see the Sup-
porting Information). The ketals were separated chromatogra-
phically, and their ratio, determined by isolation, was 2.5:1.
(5R,6S)-5-[8-(1,3-Ben zodioxol-5-yl)-1-octyn yl]-3-(1,1-dim -
eth yleth yl)-8,8-d ieth yl-2,2,6-tr im eth yl-4,7-d ioxa -3,8-d isi-
la d eca n e (11). t-Bu2SiHCl (0.16 mL, 0.79 mmol) was added
dropwise to a stirred solution of alcohol 10 (0.261 g, 0.62 mmol)
and imidazole (0.110 g, 1.61 mmol) in CH2Cl2 (2.5 mL). After
18 h, water (2 mL) and CH2Cl2 (10 mL) were added, and the
organic layer was separated and washed with brine, dried
(MgSO4), and evaporated. Flash chromatography of the residue
over silica gel (1 × 15 cm), using 5% EtOAc-hexane, gave 11
(0.287 g, 82%) as a colorless oil: [R]D -11.97 (c 0.81, CH2Cl2);
FTIR (CH2Cl2 cast) 2095 cm-1; 1H NMR (CDCl3, 360 MHz) 0.62
(q, J ) 7.5 Hz, 6 H), 0.97 (t, J ) 7.5 Hz, 9 H), 1.02 (s, 9 H),
1.03 (s, 9 H), 1.24 (d, J ) 6.0 Hz, 3 H), 1.28-1.62 (m, 8 H),
2.19 (dt, J ) 7.0, 1.5 Hz, 2 H), 2.53 (apparent t, J ) 7.0 Hz, 2
H), 3.81 (dq, J ) 6.0, 4.5 Hz, 1 H), 4.11 (s, 1 H), 4.27 (dt, J )
4.5, 1.5 Hz, 1 H), 5.92 (s, 2 H), 6.60-6.74 (m, 3 H); 13C NMR
(CDCl3, 100.6 MHz) δ 4.9 (t′), 6.9 (q′), 18.6 (q′), 18.7 (t′), 19.9
(s′), 20.3 (s′), 27.3 (q′), 27.5 (q′), 28.5 (t′), 28.7 (two overlapping
t′), 31.6 (t′), 35.6 (t′), 71.6 (d′), 72.5 (d′), 79.9 (s′), 85.8 (s′), 100.7
(t′), 108.0 (d′), 108.8 (d′), 121.0 (d′), 136.7 (s′), 145.4 (s′), 147.5
(s′); exact mass (electrospray) m/z calcd for C32H56NaO4Si2
583.361487, found 583.361501.
(2S,3R)-11-(1,3-Ben zod ioxol-5-yl)-3-[[bis(1,1-d im eth yl-
eth yl)silyl]oxy]-4-u n d ecyn -2-ol (12). CF3CO2H20 (75 µL,
0.97 mmol) was added dropwise to a stirred solution of silane
11 (205 mg, 0.37 mmol) in THF (2.4 mL) and water (0.4 mL).
After 2 h, saturated aqueous NaHCO3 (1 mL) and Et2O (5 mL)
were added. The layers were separated, and the aqueous layer
was extracted with Et2O. The combined organic extracts were
washed with brine, dried (MgSO4), and evaporated. Flash
chromatography of the residue over silica gel (1 × 15 cm), using
15% EtOAc-hexane, gave 12 (142 mg, 87%) as a colorless oil:
FTIR (CH2Cl2 cast) 2101 cm-1; 1H NMR (CDCl3, 360 MHz) 1.01
(s, 9 H), 1.03 (s, 9 H), 1.24 (d, J ) 6.5 Hz, 3 H), 1.27-1.62 (m,
8 H), 2.21 (dt, J ) 7.0, 2.0 Hz, 2 H), 2.29 (d, J ) 5.0 Hz, 1 H),
2.52 (apparent t, J ) 7.5 Hz, 2 H), 3.81 (m, 1 H), 4.11 (s, 1 H),
4.36 (dt, J ) 4.0, 2.0 Hz, 1 H), 5.92 (s, 2 H), 6.60-6.74 (m, 3
H); 13C NMR (CDCl3, 100.6 MHz) 17.8 (q′), 18.7 (t′), 19.8 (s′),
21.2 (s′), 27.29 (q′), 27.34 (q′), 28.5 (t′), 28.6 (t′), 28.7 (t′), 31.6
(t′), 35.6 (t′), 70.8 (d′), 71.3 (d′), 77.5 (s′), 87.7 (s′), 100.7 (t′),
108.0 (d′), 108.8 (d′), 121.0 (d′), 136.7 (s′), 145.4 (s′), 147.5 (s′);
exact mass (electrospray)m/zcalcd for C26H42NaO4Si469.275008,
found 469.275388.
5-(7-Octyn yl)-1,3-ben zod ioxole (8). (a ) 5-(8,8-Dibr om o-
7-octen yl)-1,3-ben zod ioxole. A solution of CBr4 (4.63 g,
13.96 mmol) in CH2Cl2 (25 mL) was added dropwise to a stirred
and cooled (-20 °C) solution of Ph3P (3.66 g, 14.0 mmol) in
CH2Cl2 (25 mL). Stirring was continued for 15 min at -20 °C,
and the reaction flask was then transferred to a cold bath at
-78 °C. A solution of aldehyde 9 (1.50 g, 6.35 mmol) and Et3N
(0.87 mL, 6.35 mmol) in CH2Cl2 (10 mL) was added dropwise
over 10 min at -78 °C. The cold bath was removed, and
stirring was continued for 2 h. The mixture was filtered
through a pad (2 × 3 cm) of flash chromatography silica gel,
using Et2O as a rinse. Evaporation of the combined filtrates
and flash chromatography of residue over silica, using 5%
EtOAc-hexane, gave 5-(8,8-dibromo-7-heptenyl)-1,3-benzo-
dioxole (2.28 g, 92%) as a yellowish oil: FTIR (CHCl3 cast)
3010, 1502 cm-1; 1H NMR (CDCl3, 300 MHz) 1.28-1.40 (m, 8
H), 1.58 (m, 2 H), 2.09 (q, J ) 7.0 Hz, 2 H), 2.51 (t, J ) 7.0 Hz,
2 H), 5.92 (s, 2 H), 6.41 (t, J ) 7.0 Hz, 1 H), 6.60-6.78 (m, 3
H); 13C NMR (CDCl3, 75.5 MHz) δ 27.7 (t′), 28.8 (t′), 28.9 (t′),
31.6 (t′), 33.0 (t′), 35.6 (t′), 88.6 (s′), 100.7 (t′), 108.1 (d′), 108.9
(d′), 121.1 (d′), 136.6 (s′), 138.9 (d′), 145.5 (s′), 147.5 (s′); exact
mass m/zcalcd for C15H1879Br81BrO2 389.95530, found 389.96536.
(b) 5-(7-Octyn yl)-1,3-ben zod ioxole (8). n-BuLi (2.5 M in
hexanes, 3.70 mL, 9.25 mmol) was added dropwise to a stirred
and cooled (-78 °C) solution of the above dibromoalkene (1.445
g, 3.7 mmol) in dry THF (35 mL). Stirring at -78 °C was
continued for 1 h, the cold bath was removed, and stirring was
continued for 2 h. Saturated aqueous NH4Cl (5 mL) and Et2O
(20 mL) were added, and the organic layer was washed with
water and brine, dried (MgSO4), and evaporated. Flash chro-
matography of the residue over silica gel (2 × 15 cm), using
25% PhMe-hexane, gave 8 (0.809 g, 95%) as a colorless oil:
FTIR (CHCl3 cast) 3297, 2116 cm-1 1H NMR (CDCl3, 300
;
MHz) 1.28-1.64 (m, 8 H), 1.95 (t, J ) 2.5 Hz, 1 H), 2.19 (td,
J ) 7.0, 2.5 Hz, 2 H), 2.53 (apparent t, J ) 7.0 Hz, 2 H), 5.92
(s, 2 H), 6.60-6.78 (m, 3 H); 13C NMR (CDCl3, 75.5 MHz) δ
18.4 (t′), 28.4 (t′), 28.6 (t′), 28.6 (t′), 31.6 (t′), 35.6 (t′), 68.2 (d′),
84.7 (s′), 100.7 (t′), 108.0 (d′), 108.8 (d′), 121.0 (d′), 136.6 (s′),
145.4 (s′), 147.5 (s′); exact mass m/z calcd for
C15H18O2
230.13068, found 230.13067.
(2S,3R)-11-(1,3-Ben zod ioxol-5-yl)-2-[(tr ieth ylsilyl)oxy]-
4-u n d ecyn -3-ol (10). n-BuLi (2.5 M in hexanes, 0.40 mL, 1.0
mmol) was added dropwise to a stirred and cooled (-78 °C)
solution of acetylene 8 (0.220 g, 0.95 mmol) in dry THF (5 mL).
The mixture was stirred at -78 °C for 30 min, and then a
solution of aldehyde 7 (0.180 g, 0.95 mmol) in dry THF (1.5
mL) was added dropwise over 5 min. Stirring at -78 °C was
continued for 3 h, and then saturated aqueous NH4Cl (1 mL)
and Et2O (10 mL) were added. The aqueous layer was
extracted with Et2O, and the combined organic extracts were
washed with water and brine, dried (MgSO4), and evaporated.
Flash chromatography of the residue over silica gel (2 × 15
cm), using 10% EtOAc-hexane, gave alcohol 10 (0.236 g, 59%)
Im id a zole-1-ca r boxylic Acid (1S,2R)-O-[10-(1,3-Ben zo-
d ioxol-5-yl)-2-[[bis(1,1-d im eth yleth yl)silyl]oxy]-1-m eth yl-
3-d ecyn yl] Ester (13) a n d Se-P h en yl (1S,2R)-O-[10-(1,3-
Ben zod ioxol-5-yl)-2-[[bis(1,1-d im eth yleth yl)silyl]oxy]-1-
m eth yl-3-d ecyn yl]ca r bon oselen oa te (14). The following
method for making the selenocarbonate is based on the
procedure given in ref 15.
A solution of alcohol 12 (19 mg, 0.0582 mmol) in ClCH2-
CH2Cl (1 mL) was added to a stirred solution of Im2CO (24
mg, 0.1480 mmol) in ClCH2CH2Cl (1 mL). After 4 h, PhSeH
(19) Clive, D. L. J .; Wickens, P. L.; Sgarbi, P. W. M. J . Org. Chem.
1996, 61, 7426-7437.
(20) Cf. J ones, T. K.; Reamer, R. A.; Desmond, R.; Mills, S. G. J .
Am. Chem. Soc. 1990, 112, 2998-3017.

4844 J . Org. Chem., Vol. 66, No. 14, 2001
Clive and Ardelean
(46 mg, 0.286 mmol) in ClCH2CH2Cl (1 mL) was added to the
resulting imidazole-1-carboxylic acid (1S,2R)-O-[10-(1,3-ben-
zodioxol-5-yl)-2-[[bis(1,1-dimethylethyl)silyl]oxy]-1-methyl-3-
decynyl] ester (13), and the solution was refluxed overnight.
The mixture was cooled to room temperature, and water and
CH2Cl2 were added. The organic layer was separated, washed
with brine, dried (MgSO4), and evaporated. Flash chromatog-
raphy of the residue over silica gel (0.5 × 15 cm), using 15%
EtOAc-hexane, gave 14 (26 mg, 74%) as a colorless oil: FTIR
(s, 9 H), 1.20-1.40 (m, 7 H), 1.50-1.60 (m, 7 H), 2.98 (t, J )
7.5 Hz, 2 H), 2.98 (m, 1 H), 4.20 (d, J ) 5.5 Hz, 1 H), 4.47 (q,
J ) 7.0 Hz, 1 H), 4.51 (ABq, J ) 11.5 Hz, ∆νAB ) 170.5 Hz, 2
H), 5.15 (d, J ) 3.9 Hz, 1 H), 5.92 (s, 2 H), 6.60-6.73 (m, 3 H),
7.25-7.40 (m, 5 H); 13C NMR (CDCl3, 125.7 MHz) 20.3 (q′),
21.2 (s′), 21.8 (s′), 25.5 (t′), 28.03 (q′), 28.05 (t′), 28.1 (q′), 29.3
(t′), 29.8 (t′), 31.5 (t′), 31.9 (t′), 35.8 (t′), 52.3 (d′), 69.7 (t′), 84.2
(d′), 87.3 (d′), 100.7 (t′), 105.2 (d′), 108.0 (d′), 108.8 (d′), 121.0
(d′), 127.5 (d′), 128.21 (d′), 128.25 (d′), 136.7 (s′), 138.1 (s′), 145.4
(s′), 147.4 (s′); exact mass (electrospray) m/z calcd for C27H44O5-
Si 476.29581, found 476.29526. TROESY NMR measurements
showed an NOE between C(4)H and C(6)H, and between
C(3a)H and C(6a)H.
1
(CDCl3 cast) 1726 cm-1; H NMR (CDCl3, 360 MHz) 1.02 (s,
18 H), 1.40 (d, J ) 6.5 Hz, 3 H), 1.27-1.60 (m, 8 H), 2.19 (dt,
J ) 7.0, 2.0 Hz, 2 H), 2.52 (apparent t, J ) 7.5 Hz, 2 H), 4.10
(s, 1 H), 4.63 (m, 1 H), 5.08 (dq, J ) 6.5, 2.0 Hz, 1 H), 5.92 (s,
2 H), 6.60-6.74 (m, 3 H), 7.32-7.40 (m, 3 H), 7.58-7.63 (m, 2
H); 13C NMR (CDCl3, 125.7 MHz) 14.2 (q′), 18.6 (t′), 20.0 (s′),
20.3 (s′), 27.3 (q′), 27.5 (q′), 28.4 (t′), 28.7 (two overlapping t′),
31.7 (t′), 35.7 (t′), 68.1 (d′), 76.2 (s′), 78.0 (d′), 87.3 (s′), 100.7
(t′), 108.1 (d′), 108.9 (d′), 121.1 (d′), 126.3 (s′), 129.0 (d′), 129.3
(d′), 135.8 (d′), 136.7 (s′), 145.5 (s′), 147.5 (s′), 166.5 (s′); exact
mass (electrospray) m/z calcd for C33H46NaO480SeSi 653.217744,
found 653.217657.
The intermediate (1S,2R)-O-[10-(1,3-benzodioxol-5-yl)-2-
[[bis(1,1-dimethylethyl)silyl]oxy]-1-methyl-3-decynyl] ester (13)
had: 1H NMR (CDCl3, 360 MHz) δ 1.02 (s, 18 H), 1.47 (d, J )
6.9 Hz, 3 H), 1.25-1.40 (m, 8 H), 2.19 (dt, J ) 7.0, 2.0 Hz, 2
H), 2.53 (t, J ) 7.5 Hz, 2 H), 4.10 (s, 1 H), 4.70-4.73 (m, 1 H),
5.12-5.20 (m, 1 H), 5.92 (s, 2 H), 6.60-6.73 (m, 3 H), 7.08 (br
s, 1 H), 7.43 (br s, 1 H), 8.17 (br s, 1 H).
(2S,3R,4S,5S)-4-[7-(1,3-Ben zodioxol-5-yl)h eptyl]-2-m eth -
yl-5-(ph en ylm eth oxy)tetr ah ydr ofu r an -3-ol (18),(3S,4R,5S)-
3-[7-(1,3-Ben zod ioxol-5-yl)h ep t yl]t et r a h yd r o-5-m et h yl-
fu r a n -2,4-d iol (19), a n d (3S,4R,5S)-3-[7-(1,3-Ben zod ioxol-
5-y l)h e p t y l]d ih y d r o -4-h y d r o x y -5-m e t h y l-2(3H )-fu r -
a n on e (1). Bu4NF (1.0 M solution in THF, 50 µL, 0.05 mmol)
was added to a stirred, hot (60 °C) solution of (3R,3aS,4S,6S,-
6aR)-3-[6-(1,3-benzodioxol-5-yl)hexyl]-2,2-bis(1,1-dimethyleth-
yl)hexahydro-6-methyl-4-(phenylmethoxy)furo[3,4-d]-1,2-ox-
asilole (17) (7.0 mg, 0.0123 mmol) in DMF (2 mL). Stirring
was continued for 4 h, and the mixture allowed to cool to room
temperature. Water (1 mL) and Et2O (5 mL) were added, and
the aqueous layer was extracted with Et2O. The combined or-
ganic extracts were washed with water and brine, dried (Mg-
SO4), and evaporated to afford crude alcohol 18 (3.7 mg, 71%).
Pd/C (10%, 3 mg) was added to a solution of crude alcohol
18 in MeOH (2 mL) and the mixture was stirred under H2
(balloon) for 15 min. The mixture was filtered through a pad
(1 × 2 cm) of Celite, which was washed with MeOH (5 mL).
The filtrate was evaporated, and the resulting crude product
(unstable to acid) was dissolved in PhH (2.5 mL). Fe´tizon
reagent21 (20 mg, ca. 0.035 mmol) was added, and the mixture
was refluxed for 4 h, cooled, and filtered through a sintered
disk. Evaporation of the filtrate and flash chromatography of
the residue over silica gel (0.5 × 15 cm), using 30% EtOAc-
hexane, gave 1 (2.2 mg, 53% over the last three steps) as a
colorless oil, whose 1H NMR and 13C NMR were identical,
within experimental error, to the published1a data, the cor-
respondence being particularly clear in the case of the 13C
spectrum: 1H NMR (CDCl3, 360 MHz) δ 1.20-1.83 [m,
including d at δ 1.74 (J ) 4.5 Hz), 10 H in all], 1.34 (d J ) 6.8
Hz, 3 H), 2.52 (t, J ) 7.8 Hz, 2 H), 2.60 (dt, J ) 9.6, 5.5 Hz, 1
H), 4.19 (br t, J ) 4.7 Hz, 1 H), 4.51 (dq, J ) 6.76, 1.0 Hz, 1
H), 5.92 (s, 2 H), 6.61 (d, J ) 7.9, 1.7 Hz, 1 H), 6.67 (d, J ) 1.6
Hz, 1 H), 6.72 (d, J ) 7.9 Hz, 1 H); 13C NMR (125.7 MHz,
CDCl3) δ (values in brackets are the reported1a values obtained
at 50 MHz in CDCl3) 18.17 (q′) (18.1); 23.36 (t′) (23.3); 27.69
(t′) (27.6); 29.05 (t′) (29.0); 29.27 (t′) (29.2); 29.50 (t′) (29.4);
31.69 (t′) (31.7); 35.68 (t′) (35.6); 43.78 (d′) (43.7); 73.99 (d′)
(73.9); 82.36 (d′) (82.4); 100.74 (t′) (100.6); 108.09 (d′) (108.2);
108.90 (d′) (108.8); 121.09 (d′) (121.0); 136.74 (s′) (136.7); 145.47
(s′) (145.4); 147.51 (s′) (147.4); 177.08 (s′) (177.2). The synthetic
material had: [R]25546 +26 (c 0.3, MeOH), [R]25D +16.6 (c 0.22,
(3R,3a S,6S,6a R)-3-[6-(1,3-Ben zod ioxol-5-yl)h exyl]-2,2-
b is(1,1-d im et h ylet h yl)t et r a h yd r o-6-m et h ylfu r o[3,4-d ]-
1,2-oxa silol-4(2H)-on e (15). A solution of Ph3SnH (15 mg,
0.040 mmol) and AIBN (1 mg, 0.006 mmol) in PhH (2.5 mL)
was added over 7 h by a syringe pump to a stirred and
refluxing solution of phenylseleno carbonate 14 (20 mg, 0.033
mmol) in PhH. Refluxing was continued for 1 h after the end
of addition, and the mixture was then cooled to room temper-
ature. Evaporation of the solvent and flash chromatography
of the residue over silica gel (0.5 × 15 cm), using 20% EtOAc-
hexane, gave 15 (13 mg, 79%) as a colorless oil: [R]D 10.88 (c
1
2.7, CH2Cl2); FTIR (CDCl3 cast) 1768 cm-1; H NMR (CDCl3,
360 MHz) 1.02 (s, 18 H), 1.30-1.80 (m, 10 H), 2.31 (m, 1 H),
2.53 (t, J ) 7.5 Hz, 2 H), 3.19 (dd, J ) 10.0, 5.3 Hz, 1 H), 4.26
(d, J ) 5.3 Hz, 1 H), 4.62 (q, J ) 6.9 Hz, 1 H), 5.92 (s, 2 H),
6.60-6.73 (m, 3 H); 13C NMR (CDCl3, 125.7 MHz) 18.9 (q′),
20.5 (s′), 21.4 (s′), 25.1 (t′), 25.3 (d′), 27.6 (q′), 27.8 (q′), 29.1
(t′), 29.4 (t′), 31.6 (t′), 31.7 (t′), 35.7 (t′), 43.8 (d′), 81.9 (d′), 82.6
(d′), 100.6 (t′), 108.0 (d′), 108.8 (d′), 121.0 (d′), 136.8 (s′), 145.4
(s′), 147.4 (s′), 175.8 (s′); exact mass (electrospray) m/z calcd
for C27H42NaO5Si 497.269923, found 497.270380.
(3R,3a S,6S,6a R)-3-[6-(1,3-Ben zod ioxol-5-yl)h exyl]-2,2-
b is(1,1-d im et h ylet h yl)h exa h yd r o-6-m et h ylfu r o[3,4-d ]-
1,2-oxa silol-4-ol (16) a n d (3R,3a S,4S,6S,6a R)-3-[6-(1,3-
B e n zo d io x o l-5-y l)h e x y l]-2,2-b is (1,1-d im e t h y le t h y l)-
h exa h yd r o-6-m et h yl-4-(p h en ylm et h oxy)fu r o[3,4-d ]-1,2-
oxa silole (17). DIBAL-H (1 M in PhMe, 26 µL, 0.026 mmol)
was added dropwise to a stirred and cooled (-78 °C) solution
of lactone 15 (12 mg, 0.025 mmol) in PhMe (1 mL). After 15
min, the reaction was complete (TLC control, silica, 30%
EtOAc-hexane), and MeOH (0.1 mL) was added, followed by
water (0.1 mL) and Celite (0.2 g). The cooling bath was
removed, and stirring was continued for 15 min. The mixture
was filtered through a pad (2 × 1 cm) of Celite, using EtOAc
as a rinse. Evaporation of the filtrate gave the sensitive lactol
1616 (12 mg, 100%), which was used immediately in the next
step. Attempted flash chromatography over silica gel caused
decomposition.
MeOH) [lit.1a [R]25 3.7 (MeOH)].
546
Ack n ow led gm en t. We thank the Natural Sciences
and Engineering Research Council of Canada and
Merck Frosst (Montreal) for financial support. We also
thank Dr. P. L. Beaulieu and Colette Boucher of Bio-
Me´ga Boehringer Ingelheim (Montreal) for measuring
the optical purity of compound 10. E.-S.A. held a
Graduate Research Assistantship.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of new
compounds and experimental procedures for the determination
of the relative stereochemistry and optical purity of 10. This
material is available free of charge via the Internet at
http://pubs.acs.org.
BnOH (10 mg, 9.2 mmol) in CH2Cl2 (0.5 mL) was added to
a stirred solution of the above lactol (12 mg, 0.025 mmol) in
CH2Cl2 (1 mL), followed by a crystal of TsOH‚H2O. After 10
min, saturated aqueous NaHCO3 (1 mL) and CH2Cl2 (5 mL)
were added, and the organic layer was separated, washed with
brine, dried (MgSO4), and evaporated. Flash chromatography
of the residue over silica gel (0.5 × 15 cm), using 10% EtOAc-
hexane, gave 17 (14 mg, 98%) as a colorless oil: FTIR (CDCl3
cast) 1768 cm-1; 1H NMR (CDCl3, 360 MHz) 1.01 (s, 9 H), 1.02
J O010206Y
(21) Balogh, V.; Fe´tizon, M.; Golfier, M. J . Org. Chem. 1971, 36,
1339-1341.